chr14-73961297-A-T

Variant names:

• chr14-73961297-A-T
• rs2074930
• NM_182476.3:c.1016A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182476.3(COQ6):​c.1016A>T​(p.Asp339Val) variant causes a missense change. The variant allele was found at a frequency of 0.0599 in 1,614,026 control chromosomes in the GnomAD database, including 5,430 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D339G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.085 (908 hom., cov: 32)
  • Exomes 𝑓: 0.057 (4522 hom.)
• Consequence: COQ6 NM_182476.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.99
• Publications: 26 publications found

Genes affected

COQ6 (HGNC:20233): (coenzyme Q6, monooxygenase) The protein encoded by this gene belongs to the ubiH/COQ6 family. It is an evolutionarily conserved monooxygenase required for the biosynthesis of coenzyme Q10 (or ubiquinone), which is an essential component of the mitochondrial electron transport chain, and one of the most potent lipophilic antioxidants implicated in the protection of cell damage by reactive oxygen species. Knockdown of this gene in mouse and zebrafish results in decreased growth due to increased apoptosis. Mutations in this gene are associated with autosomal recessive coenzyme Q10 deficiency-6 (COQ10D6), which manifests as nephrotic syndrome with sensorineural deafness. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2012]

ENTPD5 (HGNC:3367): (ectonucleoside triphosphate diphosphohydrolase 5 (inactive)) The protein encoded by this gene is similar to E-type nucleotidases (NTPases)/ecto-ATPase/apyrases. NTPases, such as CD39, mediate catabolism of extracellular nucleotides. ENTPD5 contains 4 apyrase-conserved regions which is characteristic of NTPases. [provided by RefSeq, Jan 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014210045).
• BP6: Variant 14-73961297-A-T is Benign according to our data. Variant chr14-73961297-A-T is described in ClinVar as Benign. ClinVar VariationId is 128833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	NM_182476.3	MANE Select	c.1016A>T	p.Asp339Val	missense	Exon 9 of 12	NP_872282.1
	COQ6	NM_001425255.1		c.1016A>T	p.Asp339Val	missense	Exon 9 of 11	NP_001412184.1
	COQ6	NM_182480.3		c.941A>T	p.Asp314Val	missense	Exon 9 of 12	NP_872286.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COQ6	ENST00000334571.7	TSL:1 MANE Select	c.1016A>T	p.Asp339Val	missense	Exon 9 of 12	ENSP00000333946.2
	COQ6	ENST00000554341.6	TSL:1	n.*621A>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000450736.2
	COQ6	ENST00000554341.6	TSL:1	n.*621A>T		3_prime_UTR	Exon 8 of 11	ENSP00000450736.2

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12869 AN: 152036 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0652

GnomAD2 exomes AF: 0.0784 AC: 19701 AN: 251402 AF XY: 0.0762

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0423

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0486

GnomAD4 exome AF: 0.0573 AC: 83768 AN: 1461872 Hom.: 4522 Cov.: 32 AF XY: 0.0583 AC XY: 42382 AN XY: 727240

African (AFR) AF: 0.167 AC: 5602 AN: 33480

American (AMR) AF: 0.0437 AC: 1954 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 783 AN: 26136

East Asian (EAS) AF: 0.318 AC: 12637 AN: 39692

South Asian (SAS) AF: 0.119 AC: 10246 AN: 86252

European-Finnish (FIN) AF: 0.0163 AC: 869 AN: 53420

Middle Eastern (MID) AF: 0.0364 AC: 210 AN: 5768

European-Non Finnish (NFE) AF: 0.0429 AC: 47714 AN: 1112008

Other (OTH) AF: 0.0621 AC: 3753 AN: 60394

GnomAD4 genome AF: 0.0848 AC: 12898 AN: 152154 Hom.: 908 Cov.: 32 AF XY: 0.0850 AC XY: 6321 AN XY: 74392

African (AFR) AF: 0.161 AC: 6661 AN: 41492

American (AMR) AF: 0.0454 AC: 694 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.321 AC: 1656 AN: 5156

South Asian (SAS) AF: 0.127 AC: 611 AN: 4818

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2776 AN: 67996

Other (OTH) AF: 0.0674 AC: 142 AN: 2108

Alfa AF: 0.0529 Hom.: 328

Bravo AF: 0.0927

TwinsUK AF: 0.0426 AC: 158

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.152 AC: 668

ESP6500EA AF: 0.0430 AC: 370

ExAC AF: 0.0818 AC: 9934

Asia WGS AF: 0.175 AC: 605 AN: 3478

EpiCase AF: 0.0377

EpiControl AF: 0.0347

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.020	N
PhyloP100		5.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.36	T
Sift4G	Benign	0.39	T
Polyphen		0.0020	B
Vest4		0.40
MPC		1.1
ClinPred		0.027	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.75
Mutation Taster		=40/60	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2074930; hg19: chr14-74428000; COSMIC: COSV53178052; COSMIC: COSV53178052;